Emerging therapies for mitochondrial disorders.

Helen Nightingale,Patrick F Chinnery,Gerald Pfeffer,Rita Horvath,David Bargiela

doi:10.1093/brain/aww081

Abstract

Mitochondrial disorders are a diverse group of debilitating conditions resulting from nuclear and mitochondrial DNA mutations that affect multiple organs, often including the central and peripheral nervous system. Despite major advances in our understanding of the molecular mechanisms, effective treatments have not been forthcoming. For over five decades patients have been treated with different vitamins, co-factors and nutritional supplements, but with no proven benefit. There is therefore a clear need for a new approach. Several new strategies have been proposed acting at the molecular or cellular level. Whilst many show promise in vitro, the clinical potential of some is questionable. Here we critically appraise the most promising preclinical developments, placing the greatest emphasis on diseases caused by mitochondrial DNA mutations. With new animal and cellular models, longitudinal deep phenotyping in large patient cohorts, and growing interest from the pharmaceutical industry, the field is poised to make a breakthrough.

Highlights

Mitochondria are complex intracellular organelles that play a central role in cell homeostasis (Wallace, 1999)
This review considers each, structured into four sections (Fig. 1): manipulating DNA; new protein delivery; small molecule pharmaceuticals; and stem cell approaches
The past 5 years have seen several new approaches developing through our understanding of the molecular pathogenesis of mitochondrial diseases

Summary

Introduction

Mitochondria are complex intracellular organelles that play a central role in cell homeostasis (Wallace, 1999). Deoxyribonucleoside supplementation in a knock-in mouse model of thymidine kinase 2 (TK2) deficiency increased mtDNA copy number, improved mitochondrial respiratory chain function, and prolonged life span (Garone et al, 2014). Results from two case reports of infusion of thymidine phosphorylase encapsulated in erythrocytes for patients with MNGIE demonstrated initial reductions in toxic product levels post transplantation and some reported clinical improvement. NAD + supplementation with nicotinamide riboside has produced promising biochemical and clinical improvements in two mitochondrial myopathy murine models; a nuclear gene (Sco2) knockout/knockin mouse (Cerutti et al, 2014), and the Deletor mouse possessing a nuclear gene mutation resulting in mtDNA deletions (Khan et al, 2014). This will hopefully provide a definitive answer to the role of exercise training in this context

Conclusion

Findings

Literature search strategy